Article

Anderson PL, Kiser JJ, Gardner EM, Rower JE, Meditz A, Grant RM. Pharmacological considerations for tenofovir and emtricitabine to prevent HIV infection

Department of Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO, USA.
Journal of Antimicrobial Chemotherapy (Impact Factor: 5.31). 11/2010; 66(2):240-50. DOI: 10.1093/jac/dkq447
Source: PubMed
ABSTRACT
The use of antiretroviral medications in HIV-negative individuals as pre-exposure prophylaxis (PrEP) is a promising approach to prevent HIV infection. Tenofovir disoproxil fumarate (TDF) and emtricitabine exhibit desirable properties for PrEP including: favourable pharmacokinetics that support infrequent dosing; few major drug-drug or drug-food interactions; an excellent clinical safety record; and pre-clinical evidence for efficacy. Several large, randomized, controlled clinical trials are evaluating the safety and efficacy of TDF and emtricitabine for this new indication. A thorough understanding of variability in drug response will help determine future investigations in the field and/or implementation into clinical care. Because tenofovir and emtricitabine are nucleos(t)ide analogues, the HIV prevention and toxicity effects depend on the triphosphate analogue formed intracellularly. This review identifies important cellular pharmacology considerations for tenofovir and emtricitabine, which include drug penetration into relevant tissues and cell types, race/ethnicity/pharmacogenetics, gender, cellular activation state and appropriate episodic or alternative dosing strategies based on pharmacokinetic principles. The current state of knowledge in these areas is summarized and the future utility of intracellular pharmacokinetics/pharmacodynamics for the PrEP field is discussed.

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Pharmacological considerations for tenofovir and emtricitabine
to prevent HIV infection
Peter L. Anderson
1
*, Jennifer J. Kiser
1
, Edward M. Gardner
2,3
, Joseph E. Rower
1
, Amie Meditz
2
and Robert M . Grant
4
1
Department of Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO, USA;
2
Division of Infectious Diseases, University of
Colorado Denver, Aurora, CO, USA;
3
Denver Public Health, Denver, CO, USA;
4
Gladstone Institute of Virology and Immunology, University
of California San Francisco, CA, USA
*Corresponding author. E-mail: peter.anderson@ucdenver.edu
The use of antiretroviral medications in HIV-negative individuals as pre-exposure prophylaxis (PrEP) is a prom-
ising approach to prevent HIV infection. Tenofovir disoproxil fumarate (TDF) and emtricitabine exhibit desirable
properties for PrEP including: favourable pharmacokinetics that support infrequent dosing; few major drug-drug
or drug-food interactions; an excellent clinical safety record; and pre-clinical evidence for efficacy. Several large,
randomized, controlled clinical trials are evaluating the safety and efficacy of TDF and emtricitabine for this new
indication. A thorough understanding of variability in drug response will help determine future investigations in
the field and/or implementation into clinical care. Because tenofovir and emtricitabine are nucleos(t)ide ana-
logues, the HIV prevention and toxicity effects depend on the triphosphate analogue formed intracellularly.
This review identifies important cellular pharmacology considerations for tenofovir and emtricitabine, which
include drug penetration into relevant tissues and cell types, race/ethnicity/pharmacogenetics, gender, cellular
activation state and appropriate episodic or alternative dosing strategies based on pharmacokinetic principles.
The current state of knowledge in these areas is summarized and the future utility of intracellular pharmaco-
kinetics/pharmacodynamics for the PrEP field is discussed.
Keywords: clinical pharmacology, intracellular pharmacology, pharmacokinetics, pharmacodynamics, pharmacogenomics,
nucleoside analogue pharmacology
Introduc tion
Although HIV prevention strategies such as promotion of safe sex
practices and clean needle exchange programmes are effective,
additional approaches are needed to help reduce the number of
new HIV infections, which are estimated at 2.7 million cases
annually.
1,2
The ideal prevention tool would be a protective
vaccine, but the feasibility and timelines for a highly effective
HIV vaccine remain unclear.
3
A new hope for a powerful HIV prevention tool has emerged
in chemoprophylaxis with antiretroviral medications, referred
to as pre-exposure prophylaxis (PrEP).
4 6
PrEP is the use of
antiretroviral medications in HIV-negative persons to prevent
HIV infection should HIV exposure take place. Antiretroviral
drugs are currently used for HIV prevention in other settings,
including after high-risk HIV exposures such as needlesticks
[post-exposure prophylaxis (PEP)], rape or high-risk sexual
exposures [non-occupational PEP (nPEP)] or for prevention of
mother to child transmission (PMTCT).
7 9
One of the differences between the prevention uses listed
above and PrEP is that the target population for PrEP may not
have the same imminent risk of HIV exposure and may be
young adults in prime health.
10
For these reasons, PrEP will
require a very low toxicity profile along with proven benefit for
an acceptable riskbenefit balance. Until recently there were
few antiretroviral agents that provided an adequate safety or tol-
erability profile for an acceptable riskbenefit ratio. This situation
is changing, however, as newer agents with more favourable
safety profiles become available.
11
In addition to excellent safety and tolerability, prototypical
PrEP agents should exhibit high cost-effectiveness, a relatively
benign HIV resistance profile should PrEP fail and pharmacokinetic
properties that support once-daily or less frequent dosing. Ideally
the pharmacokinetics should be resilient to drug interactions
and food effects, and should be effective and safe during
periods of missed doses (‘pharmacokinetically forgiving’).
1214
Drug distribution into tissues and cells susceptible to HIV infection
would be another important requirement.
Tenofovir and emtricitabine, two nucleos(t)ide analogue
reverse transcriptase inhibitors (NRTIs), have emerged as viable
PrEP agents based upon the favourable pharmacological charac-
teristics described above, considerable safety experience in
humans and compelling pre-clinical data. A number of large, ran-
domized, controlled trials in humans are under way or have been
completed to evaluate the safety and efficacy of tenofovir
or tenofovir disoproxil fumarate (TDF) with and without
# The Author 2010. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.
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doi:10.1093/jac/dkq447 Advance Access publication 30 November 2010
240
Page 1
emtricitabine as PrEP (Table 1).
6,10
The trials are taking place in
diverse regions of the world and include broad patient popu-
lations such as at-risk heterosexual women, men who have sex
with men, injection drug users and serodiscordant couples.
The global implications of the impending trial results (Table 1 )
necessitate significant reflection to help guide implementation, if
warranted. While several perspectives have already been pub-
lished regarding cost-effec tiveness models and other consider-
ations for PrEP implementation, little has been written about
the clinical and cellular pharmacology of tenofovir and emtricita-
bine in this new setting and patient population.
15,16
The purpose
of this review is to identify important clinical and cellular
pharmacology considerations for tenofovir+emtricitabine as it
relates to the use of these agents to prevent HIV infection and
to summarize the current state of knowledge in these areas.
This review focuses mostly on oral TDF+emtricitabine; readers
are directed to other important papers for review of topical
microbicides or other aspects of HIV prevention.
2,4,5,14,17 19
Clinical pharmacology for PrEP
PrEP efficacy trials such as those in Table 1 use acquisition of HIV
as a primary outcome and are consequently large and test rela-
tively few regimens and dosing strategies. Unlike therapy
research, in which plasma viral RNA levels are used to optimize
dosing in small studies, there are no surrogate markers for
prophylactic effects that can similarly guide smaller studies to
optimize dose, dosing interval or route of dosing. As a result, a
riskbenefit assessment of study results becomes increasingly
subjective with increasing variability in drug effectiveness or
toxicity. It is in the context of variable drug response that
the perspectives and role of clinical pharmacology become
most important. The goals of clinical pharmacology are to
elucidate the causes of variable drug response by examining
pharmacokinetic, pharmacodynamic and pharmacogenetic
differences among individuals.
Cellular pharmacology of tenofovir
and emtricitabine
The clinical pharmacology of tenofovir and emtricitabine
depends upon their cellular pharmacology, as these medications
are sequentially phosphorylated in cells, by host enzymes, to
the pharmacologically active triphosphate (TP) anabolites.
20,21
Tenofovir is a monophosphate analogue and thus requires
diphosphorylation to become a TP analogue [i.e. tenofovir-
diphosphate (DP)].
20
Tenofovir is polar and ionized and therefore
has poor oral bioavailability, thus the disoproxil di-ester prodrug
TDF was created to mask the two ionic regions of the phosphonic
acid to enhance penetration of gut membranes.
22
TDF is thought
to be rapidly converted by a carboxylesterase to a monoester
upon absorption across the intestinal wall and then to tenofovir
Table 1. Major clinical trials involving tenofovir or TDF+emtricitabine (adapted from reference 6)
Location Sponsor Population PrEP strategy(ies) being tested Status/expected completion
USA (CDC 4323) CDC 400 MSM daily TDF completed/2009; final
analysis/2010
Thailand (CDC 4370) CDC 2400 injecting drug users daily TDF enrolling/2010
S. Africa (CAPRISA 004) CAPRISA, FHI,
CONRAD, USAID,
LIFElab
1200 women coital-dependent topical TFV gel completed/2009; final
analysis/2010
Botswana (CDC 4940) CDC 1200 heterosexual men and
women
daily TDF/FTC (switched from
TDF early 2007)
decreased scope to focus on
safety and not efficacy/
2010
Brazil, Ecuador, Peru,
S. Africa, Thailand, USA
(iPrEX)
NIH, BMGF 3000 MSM daily TDF/FTC fully enrolled/2010
Kenya, Uganda (Partners
PrEP)
BMGF 3900 serodiscordant
heterosexual couples
daily TDF or daily TDF/FTC enrolling/2013
Kenya, Malawi, S. Africa,
Tanzania, Zambia
(FEM-PrEP)
FHI, USAID, BMGF 3900 women daily TDF/FTC enrolling/2013
S. Africa, Uganda, Zambia,
Zimbabwe (VOICE
MTN 003)
MTN, NIH 5000 women daily TDF or daily TDF/FTC or
daily topical TFV gel
enrolling/2013
Kenya, Uganda (IAVI E001
& E002)
IAVI 150 serodiscordant couples
or at risk men and women
daily TDF/FTC or twice weekly
with coital dosing TDF/FTC
fully enrolled/2010
USA (PCS 082) NICHD 99 young MSM daily TDF/FTC enrolling/2011
BMGF, Bill & Melinda Gates Foundation; CAPRISA, Centre for the AIDS Programme of Research in South Africa; FHI, Family Health International; FTC,
emtricitabine; IAVI, International AIDS Vaccine Initiative; MSM, men who have sex with men; MTN, Microbicide Trials Network; TFV, tenofovir;
USAID, United States Agency for International Development.
Review
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    • "Given that intracellular phosphorylated metabolites can have longer half-lives, certain microbicides can accumulate in cells over time. For example, intracellular PBMC concentrations are indicative of dosing over the preceding two to four weeks [23,24]. PBMC isolation from blood, however, is rather complex, costly and difficult to conduct in rural study sites. "
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